1. Technical Field
The present invention relates to stereo isomers (E) and (Z) of 4-t-butyl gabapentin and a process for the preparation of the said stereoisomers.
2. Background and Prior Art Reference
Gabapentin, (1-aminomethyl)cyclohexane-1-acetic acid is an antiepileptic drug, which has been found to have pain-relieving properties. Additionally, it is claimed to have anti-anxiety activity as also beneficial properties in treating neurodegenerative diseases like Alzheimer's. Gabapentin and its analogues are reported to exert their activity by binding to the alpha 2-delta sub unit of calcium channel.
WO 99114184 reports the synthesis of gabapentin analogues 3-methyl, 4-methyl and 3,5-dimethyl gabapentin and their biological activity. In all these analogues the aminomethyl group could preferentially occupy the equatorial position in the more stable conformation along with certain percentage in the axial position. However the exact conformation in which these bind to a receptor is not known. If the energy differences are not significant, binding with the aminomethyl group in the axial position cannot be ruled out. This document does not claim the report of t-butyl gabapentin specifically but covers it in a generic way.
The tertiary butyl group has been known as an anchoring substituent on the cyclohexane ring occupying exclusively the equatorial confirmation in the ring. Therefore, if one were to synthesize 1-aminomethyl cyclohexane-1-acetic acids with a 4-t-butyl group in cis or trans stereochemistry with respect to the aminomethyl group to obtain Z and E stereoisomer respectively it should be feasible to study better, the optimal conformation for good binding of 4-t-butyl gabapentin with the alpha 2 delta sub unit of the calcium channel.
However, prior art search revealed the report of 4-t-butyl gabapentin in documents U.S. Pat. No. 6,103,932 and WO 02100347 A2. U.S. Pat. No. 6,103,932 recites and claims 4-t-butyl gabapentin, and a pharmaceutically acceptable salts thereof or a prodrug thereof, while WO 2002100347A notes the use of t-butylgabapentin in the form of a prodrug without any example. The document also describes general synthetic methods for the preparation of alkyl gabapentin analogues having one or more alkyl substituents in the cyclohexane ring. There is no specific example describing the preparation of the compound 4-t-butylgabapentin. This patent also records the radio ligand-binding assay with the alpha 2 detla sub unit derived from porcine brain tissue giving an IC50 value of 200 micro M for 4-t-butyl gabapentin, again without stereochemistry, thus missing out a solution to the crucial and challenging issue of conformational identity in the native and bound states.
U.S. Pat. No. 6,103,932 describe various synthetic routes for the preparation gabapentin analogues where as WO 99114184 restricts itself to the use of a nitro methyl intermediate to obtain gabapentin analogues. In the former patent, two routes are employed: (a) an alkyl-substituted cyclohexanone is converted to a cyanocyclohexylidene acetic ester, which is treated with aqueous alcoholic sodium cyanide to 1-cyanocyclohexane acetic ester, which upon reduction gives an azaspirodecanone. Hydrolysis of the lactam with 1:1 HCl affords the alkyl substituted gabapentin hydrochloride. In the second route, an alkyl substituted cyclohexanone is treated with ethyl cyanoacetate and ammonia gas in methanol to afford a dicyano spiroglutarimide which is hydrolysed by hot concentrated sulphuric acid to an alkyl substituted cyclohexane-1,1-diacetic acid. The diacid is converted to the anhydride, which is opened up with methanol to give the half-ester acid. This is treated with ethyl chloroformate followed by sodium azide. Thermolysis of the acylazide gives an isocyanate which upon hydrolysis with concentrated hydrochloric acid yields the alkyl substituted gabapentin hydrochloride.
In WO 99114184, the method adopted is to add nitromethane to an alkyl substituted cyclohexylidene acetic ester, which upon catalytic reduction affords the alkyl-substituted azaspirodecanone. Hydrolysis with 6 N HCl and evaporation affords the alkyl substituted gabapentin hydrochloride.
U.S. Pat. No. 6,103,932 and PCT Int'l Application publication WO 99/14184 describe examples wherein the final products, gabapentin analogues are obtained only as hydrochloride salts. Thus, in order to establish the optimal conformation for the compound 4-t-butyl gabapentin, which can bind with the alpha2delta submit of the calcium channel, it is necessary to obtain cis and trans form of 4-t-butylgabapentin with high purity.
There are prior art references on gabapentin analogues with one or more methyl groups in the cyclohexane ring and publications on their binding activity. The ascertainment of the precise conformation in which the amino group in gabapentin binds to the alpha2delta subunit can have great significance in the design of newer analogues of gabapentin and more specifically alkyl gabapentin analogues. None of the prior art document reports cis and trans stereoisomers of 4-t-butylgabapentin and their process of preparation.